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Transglutaminase type 2 (TG2) catalyses formation of ε-(γ-glutamyl)-lysine bonds between proteins, including those of the extracellular matrix (ECM). Elevated extracellular TG2 leads to accelerated ECM deposition and reduced clearance that underlies tissue scarring and fibrosis. Many transglutaminase inhibitors exist and allowed for proof-of-concept studies in disease models, but their lack of specificity for the TG2 isoform, and/or poor pharmacokinetic/pharmacodynamic properties have limited their clinical application. We sought to develop a high affinity TG2-specific antibody against extracellular TG2 activity, with characteristics suitable for therapeutic development.Individual human TG2 domains were used to immunize mice and generate hybridomas. Supernatants were screened for inhibition of recombinant human TG2 activity, with TG2 specificity determined by ELISA.Thirteen TG2-specific, hybridoma supernatants inhibited human transamidation activity. Each hybridoma was cloned and the antibody mapped to an epitope in the TG2 core domain, using phage display panning of a TG2 fragment library. Four distinct inhibitory epitopes were determined. The most effective antibodies (AB1, DC1, and BB7) bound to amino acids 313-327 (catalytic core), with an ICWe identified a preferred inhibitory epitope in human TG2, developed antibodies with required characteristics for clinical development, and established that targeted inhibition of extracellular TG2 transamidation activity is sufficient to modify fibrotic remodelling.

Objective To explore the effect of a non-aerobic movement based activity on cognition in people with Alzheimer's type dementia (AD). Methods The sample consisted of 27 patients fulfilling the AD ICD-10 diagnostic criteria. The patient sample was randomly divided into two groups: The Exercise Group received 6 weeks movement training and comprised 15 participants with a mean age of 70.5 years (SD: 8). Control Group participated in a standard care group, which served as a control intervention, and consisted of 12 patients with an average age of 75.7 years (SD: 6.90). Cognitive functions were assessed using six computerised tests from the CANTAB, pre and post training. Data were analysed using t-tests. The false discovery rate (FDR) for multiple comparisons as well as Cohen's d effect size was used to assess the significant effects. Results Significant improvements in sustained attention, visual memory and a trend in working memory were found in the Exercise Group compared to Control Group after the 6 weeks training. In addition, after 6 weeks the Control Group deteriorated significantly in attention, while the AD patients who undertook the physical exercise showed a discrete improvement. Conclusions The present study shows that a short course of non-aerobic movement based exercise is already effective at least in some aspects of cognitive functioning in patients with AD. Although the present study is a pilot study with small samples, nevertheless, the results are promising for the further investigation and development of non-aerobic movement programmes. Copyright © 2010 John Wiley & Sons, Ltd.

In his book Metadecisions: Rehabilitating Epistemology, van Gigch makes the case for an expanded decision science. The aim of this paper is to continue the project which van Gigch initiated by first considering the limitations of the dominant ‘mathematical’ approach to the decision sciences and then rehabilitating the initial interdisciplinarity of the field. Copyright © 2008 John Wiley & Sons, Ltd.

Background: The large majority of people with dementia receive nothing in the way of specialist assessment and care at any stage of their illness. There is a particular lack of services focussed on early identification and intervention in dementia where there is the possibility of long-term harm reduction for people with dementia and their family carers. We have developed a model of care that is complementary to local systems of health and social care (The Croydon Memory Service Model [CMSM]). This is a low-cost, high-throughput, generic service to enable early identification and intervention in dementia. It is a multi-agency approach with joint ownership by health services, social services and the voluntary sector with embedded specifically-tailored approaches to primary care and minority ethnic communities. Method: We completed a service evaluation of the introduction of the CMSM in a single borough in South London. Six predefined service goals were set: high acceptability; high appropriate referral rate; successful engagement with people from minority ethnic groups; successful engagement with people with young onset dementia; focus on engagement with mild cases to enable early intervention; and an increase in the overall number of new cases of dementia seen. Mixed qualitative and quantitative methodologies were used including a description and 6-month follow-up of a cohort of 290 consecutive referrals. Results: All key predefined service goals were met: 95% acceptability; 94% appropriate referrals; successful engagement with minority ethnic groups (two-fold greater number compared with that expected from general population demographic data); 17% of referrals under 65 years of age; 68% referrals with mild or minimal dementia severity; and an estimated 63% increase in the number of new cases of dementia seen in Croydon. At 6-month follow up, those referred to the service had decreased behavioural disturbance and increased quality of life compared with baseline. Conclusions: Specific services for early dementia, which deliver diagnosis and care, can be established. These services can increase the numbers of people with early dementia identified and provided with care. Those receiving such services appear to improve in terms of quality of life and behavioural and psychological symptoms of dementia. Next steps should include the establishment of such services in other representative areas and evaluation of their effectiveness in comparison with other models of care.

Joint Forces are anticipated to play an increasingly important role in the Australian Defence Organisation. This paper provides a way of thinking about Joint Forces intended to support activities such as Joint Force capability planning and management. The central approach is that of systems thinking. This approach is applied to develop a set of core concepts associated with strategic planning for future capabilities. In particular the idea of a portfolio is introduced as a management tool for future capability planning. The concepts developed are presented as elements within a system of ideas designed for the activities of long term planning for Australia's Joint Force capabilities and the assessment and day-to-day management of these capabilities.

The iron-binding growth factor transferrin is taken up and localised in the hindgut of midgestation mouse embryos. We investigated whether the distribution of transferrin may be disturbed in mutant curly tail embryos, a proportion of which exhibit a cell proliferation defect affecting the hindgut endoderm, as part of the pathogenetic sequence leading to development of neural tube defects. Immunostaining revealed a reduction in the binding and/or uptake of transferrin by hindgut epithelial cells in affected curly tail embryos compared with their unaffected littermates. There was no apparent difference between the two embryo types, however, in the distribution or level of expression of the transferrin receptor. The receptor is expressed specifically in the hindgut endoderm of the 10.5-day embryo, although its mRNA is present in all tissues of the posterior neuropore region, suggesting posttranscriptional control of gene expression. These findings may indicate a role for transferrin binding and/or uptake in the regulation of cell proliferation in the hindgut endoderm, with a defect in this process in the curly tail mutant. However, an alternative explanation is suggested by our finding that transferrin immunostaining is more intense in the hindgut of unaffected curly tail embryos than in nonmutant CBA/Ca and CD-1 embryos. Thus, mutant embryos may increase their uptake of transferrin in an attempt to compensate for defective cell proliferation in the hindgut resulting from a defect in another pathway. Only a proportion of embryos are able to mount this compensatory response leading to the observed partial penetrance of developmental defects in the curly tail mutant mouse.